Mono- or di-substituted indole derivatives as dengue viral replication inhibitors
The present invention relates to mono- or di-substituted indole compounds, methods to prevent or treat dengue viral infections by using the compounds and also relates to use of the compounds as a medicine, more preferably for use as a medicine to treat or prevent dengue viral infections. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of dengue viral infections. The invention also relates to processes for preparation of the compounds.
1. A compound having formula 9
or a stereoisomer, pharmaceutically acceptable salt, solvate or polymorph thereof.
2. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipients, diluents or carriers.
3. A method of treating Dengue viral infection comprising administering to a patient in need thereof a compound of claim 1 .
4. The method of claim 3 , further comprising administering another antiviral agent.
5. A compound according to claim 1 , wherein said compound is: Enantiomer 9A,
wherein
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.09 (s, 3H) 3.73 (s, 3H) 3.99 (s, 3H) 6.26 (d, J=7.9 Hz, 1H) 6.55-6.62 (m, 2H) 6.91 (t, J=1.5 Hz, 1H) 6.98 (dd, J=8.4, 2.0 Hz, 1H) 7.07 (d, J=7.9 Hz, 1H) 7.13 (d, J=2.0 Hz, 1H) 7.21 (dd, J=8.8, 1.8 Hz, 1H) 7.36 (d, J=8.4 Hz, 1H) 7.59 (d, J=8.8 Hz, 1H) 8.07 (d, J=0.9 Hz, 1H) 8.55 (s, 1H) 12.29 (br s, 1H)
LC/MS (method LC-A): R t 1.20 min, MH + 583
[α] D 20 : +130.3° (c 0.555, DMF)
Chiral SFC (method SFC-E): R t 3.10 min, MH + 583, chiral purity 100%,
or a pharmaceutically acceptable salt, solvate or polymorph thereof.
6. A compound according to claim 1 , wherein said compound is: Enantiomer 9B,
wherein
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.09 (s, 3H) 3.73 (s, 3H) 3.99 (s, 3H) 6.26 (d, J=7.9 Hz, 1H) 6.56-6.62 (m, 2H) 6.92 (t, J=2.0 Hz, 1H) 6.98 (dd, J=8.1, 2.0 Hz, 1H) 7.07 (d, J=7.9 Hz, 1H) 7.13 (d, J=2.0 Hz, 1H) 7.22 (dd, J=8.8, 1.8 Hz, 1H) 7.36 (d, J=8.4 Hz, 1H) 7.59 (d, J=8.8 Hz, 1H) 8.07 (d, J=0.9 Hz, 1H) 8.55 (s, 1H) 12.30 (br s, 1H)
LC/MS (method LC-A): R t 1.20 min, MH + 583
[α] D 20 : −133.2° (c 0.5, DMF)
Chiral SFC (method SFC-E): R t 3.50 min, MH + 583, chiral purity 100%,
or a pharmaceutically acceptable salt, solvate or polymorph thereof.
7. A compound or a stereoisomer, pharmaceutically acceptable salt, solvate or polymorph thereof, according to claim 1 , wherein said compound is in a crystalline form.
8. A compound or a stereoisomer, pharmaceutically acceptable salt, or solvate thereof, according to claim 1 , wherein said compound is in an amorphous form.
9. A compound or a stereoisomer, pharmaceutically acceptable salt, or polymorph thereof, according to claim 1 , wherein said compound is in an un-solvated form, or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , which is
11. A method of treating Dengue viral infection comprising administering to a patient in need thereof a compound of claim 10 .
12. The compound of claim 1 , which is a pharmaceutically acceptable salt.
13. A method of treating Dengue viral infection comprising administering to a patient in need thereof a compound of claim 12 .